This is a second revision of a competitive renewal R01 proposal of the NEURO-HIV Epidemiologic Study in response to NIDA PAS-07-115 (Non-injection Dug Abuse and HIV/AIDS). The primary study aim is to evaluate the ability of Integrated Family and Cognitive-Behavioral Therapy-HIV Prevention Intervention (IFCBT-HIVPI) to prevent HIV among adult non-injection and injection drug users. Over a 12 week intervention interval, the IFCBT-HIVPI model coordinates the delivery of cognitive- behavioral components during 12 group sessions with a couples and family systems component during 4 couples/family sessions to address HIV risk and protective factors across multiple ecological systems. IFCBT-HIVPI main effects on primary (HIV sexual risk behaviors and HIV drug taking risk behaviors) and secondary (HIV, Chlamydia, gonorrhea, and trichomoniasis incidences and legal involvement, academic achievement, and employment) outcome domains will be evaluated. We also seek to elucidate the degree to which the development of attitudinal and behavior change skills targeted by IFCBT-HIVPI (e.g., rational beliefs, problem solving skill, adaptive couples' communication) result in post-intervention reductions of HIV, sexually transmitted infections (STIs), and HIV risk behaviors. The possibility of effect-modification is also considered with a focus on route of drug administration status (i.e., non-injector/injector), neuropsychological (e.g., executive function), and demographic (i.e., African American/white) factors. The proposed study will randomly assign 360 HIV-negative non-injection and injection drug users recruited from the original NEURO-HIV Epidemiologic Study sample to experimental (IFCBT-HIVPI) and comparison (Brief Psychoeducation Curriculum on HIV Prevention; BPEC-HIV) conditions. The composition of the original NEURO-HIV Epidemiologic Study sample provides the basis to stratify the randomized trial sample across gender and two race/ethnicity (i.e., African American and white) groups by route of drug administration status. An assessment battery comprised of a standardized interview on HIV risk behavior, neuropsychological tests, tools to assess attitudes and behavior change skills targeted by IFCBT-HIVPI, drug and STI urine testing, and serologic tests of HIV will be administered before, during, and after the intervention interval across 18-month post-intervention follow-up. Additional preliminary analyses will be conducted on the randomized trial data to: (1) derive session-by-session measures on mechanisms of change targeted by IFCBT-HIVPI via videotape coding methods; (2) characterize mechanisms of change trajectories that may then be evaluated as plausible intervention moderators if present; and (3) estimate intervention cost-effectiveness. The lack of research on science-based prevention interventions for HIV continues to be a serious gap in the literature with recent HIV trends highlighting significant health disparities, particularly among African American non-injection drug users. If successful, the proposed project should help to identify specific attitudinal and behavior change skills targeted by cognitive- behavioral and couples/family systems interventions that foster subsequent reductions in HIV, STIs and HIV risk behaviors among adult drug users at heightened disease risk.